Phyto-Nanoparticles in Osteogenesis

Abstract

Phyto-nanoparticles derived from plants are an emerging class of nanomaterials that integrate the versatility of nanotechnology with the therapeutic potential of botanical ingredients. This chapter explores the utility of phyto-nanoparticles in stimulating osteogenesis for applications in bone tissue engineering and regeneration. Plant extracts serve as sustainable nanoparticle building blocks or coatings through green synthesis approaches. Resultant phyto-nanoparticles possess multifunctional capabilities stemming from the bioactive phytochemical components that enable the modulation of osteogenic cells like mesenchymal stem cells and osteoblasts. Diverse phyto-nanoparticles based on green tea, aloe vera, curcumin, and other plant derivatives have demonstrated the ability to enhance osteoblast differentiation, proliferation, and mineralized matrix deposition. Proposed mechanisms encompass direct cell interactions, sustained intracellular delivery of osteogenic drugs, and complementary anti-inflammatory effects. Capitalizing on these osteogenic properties, researchers have designed innovative tissue engineering scaffolds, functionalized bone implants, and developed therapeutic carriers for diseases like osteoporosis using phyto-nanotechnology. Further innovations in fabrication strategies and integration with emerging technologies will realize smarter, personalized plant-based nanosystems to advance bone regeneration capabilities dramatically.

1. Introduction

Nanotechnology is a boundless frontier where science and engineering merge to revolutionize the manipulation and fabrication of materials and devices on a minuscule scale, a billionth of a meter [1]. One prominent arena in which it has permeated is medicine, giving rise to nanomedicine, which has endless possibilities in diagnostics, drug delivery, bone, and tissue regeneration. Nanomedicine utilizes the advancement, composition, assessment, and utilization of nano-sized materials and devices to detect and treat various illnesses—from cancer to heart disease to neurological disorders [2]. Nanoparticles can interact specifically with cells and tissues at the molecular level to provide accurate, potent, and long-lasting diagnoses and therapies.

Bone has an innate capacity to regenerate following trauma or disease. However, this self-healing ability is limited to minor defects and often fails for critical segmental losses arising from fracture nonunion, tumor resections, and skeletal abnormalities. Osteogenesis mediated by osteogenic cells drives bone healing and regeneration [3]. Mesenchymal stem cells (MSCs) stimulated by osteoinductive signals can differentiate into osteoblasts, representing the critical bone-forming cell population. Osteoblasts produce extracellular matrix proteins like collagen I and osteocalcin, constituting the organic matrix. Calcium deposition then forms mineralization and complex tissue formation [4]. Incorporating osteogenic cells with supportive biomaterial scaffolds enables engineered bone graft substitutes that integrate seamlessly with host vasculature and tissues after implantation. Beyond functioning as mechanical supports, biomaterial matrices provide biophysical and biochemical cues that direct survival, proliferation, and differentiation [5]. However, clinical translation needs to be improved by non-optimal scaffold properties, leading to poor cell integration and vascularization. There is tremendous scope for novel nanotechnology solutions to address these limitations in scaffold design [6]. Studies have shown that various nanoparticles, including hydroxyapatite, metallic, and rare earth nanoparticles, can support bone growth and enhance the osteogenic differentiation of mesenchymal stem cells [7]. Additionally, researchers have been investigating nanocomposite scaffolds, nanofibers, and nanoparticle-modified polymeric materials to improve tissue engineering scaffolds’ physical and chemical properties, ultimately improving osteogenesis [8].

Phyto-nanoparticles are an emerging class of nanoparticles synthesized from bioactive phytochemical (plant-derived) compounds. Ranging from 1 to 100 nm in size, these plant-inspired nanomaterials integrate the physicochemical versatility of nanoscale materials with the vast compositional diversity and therapeutic utility of botanical ingredients [9]. Phyto-nanoparticles encompass nanomaterials derived from edible and medicinal plants, including herbs, fruit and vegetable crop produce, and general botanicals. Phytochemicals are the primary building blocks or functionalizing coatings for engineering nanoparticle architectures through bottom-up self-assembly and surface modification strategies [10].

2. Materials and methods: Literature review and reference selection

This chapter on “Phyto-Nanoparticles in Osteogenesis” was meticulously assembled through a comprehensive literature review using various scientific databases, including PubMed, Scopus, and Web of Science. Search terms used involved combinations of keywords such as “phyto-nanoparticles,” “osteogenesis,” “bone regeneration,” “green synthesis,” and “plant extracts.” The initial search produced a substantial number of research articles, which were subsequently screened for relevance, with a preference for studies published within the last 5 to 10 years to ensure the inclusion of the latest research developments. Additionally, significant consideration was given to the impact factor of the journals to prioritize high-quality, peer-reviewed sources such as original research articles, review papers, and book chapters. The selected references were thoroughly examined to extract critical data concerning the types of phyto-nanoparticles, their synthesis methods, mechanisms of action, and applications in bone tissue engineering and regeneration. The chapter is structured to offer a detailed overview of the subject, beginning with an introduction to phyto-nanoparticles and their benefits. This is followed by an in-depth discussion on various phyto-nanoparticles, detailing their synthesis, properties, and roles in bone regeneration. References are meticulously integrated throughout the chapter to bolster the information presented and guide readers to further detailed resources for expanded research.

3. Phyto-nanoparticles

Phyto-nanoparticles, synthesized from plant extracts, have garnered considerable attention for their distinctive properties and wide range of potential uses in fields such as medicine, agriculture, and food production. These nanoparticles are environmentally friendly and cost-effective, and their scalability adds to their appeal as a method for synthesizing metal and metal oxide nanoparticles [11]. A multitude of methods are utilized for their synthesis. One such method is phytosynthesis, where plant extracts are employed as both environmentally friendly reducing and capping agents to create metal oxide nanoparticles [12]. Another approach is green synthesis, which harnesses plant extracts, fungi, and algae biomolecules to produce nanoparticles. Biogenic synthesis is highly regarded for its environmentally friendly nature, cost-effectiveness, and potential for easy scalability [9, 13]. Another approach to producing nanoparticles is through seed-mediated synthesis, which utilizes plant seeds. For instance, nanoparticles have successfully been synthesized using fenugreek seed extract [14]. Additionally, the Microwave-assisted method leverages microwave technology to expedite the synthesis of nanoparticles using plant extracts [15]. Ultrasonication involves accelerating nanoparticle synthesis using plant extracts [16]. The FDA has classified plant-based nanoparticles as generally recognized as safe (GRAS) and biodegradable, making them superior to other nanoparticle options for several reasons. They have lower toxicity levels and possess beneficial qualities such as greater energy efficiency and antioxidant, antifungal, antibacterial, and anticancer properties. The use of plant extracts to produce these nanoparticles is believed to contribute to these advantageous properties [17].

3.1 Phyto-nanoparticles in biomedical applications

Phyto-nanoparticles are derived from various plant sources and offer potential drug delivery, imaging, and therapy applications. One of the primary advantages of Phyto-nanoparticles is their biocompatibility and low toxicity compared to synthetic nanoparticles [18]. Plant-based nanoparticles are naturally derived and have a lower risk of causing adverse reactions in the human body. They are also biodegradable, which means they can be easily eliminated from the body after serving their purpose. This makes them an attractive alternative to conventional nanoparticles, which may have potential long-term toxicity concerns. Phyto-nanoparticles can be synthesized from various plant sources, including leaves, fruits, seeds, and roots. The synthesis process typically involves the extraction of plant compounds, followed by reducing and stabilizing metal ions to form nanoparticles [19]. Green synthesis methods, such as using plant extracts as reducing and capping agents, have gained popularity due to their simplicity, cost-effectiveness, and environmental friendliness.

One of the most promising applications of Phyto-nanoparticles in biomedicine is drug delivery (Figure 1). Plant-based nanoparticles can be engineered to encapsulate and deliver drugs to specific target sites in the body, improving therapeutic efficacy and reducing side effects [20]. Curcumin, a natural compound found in turmeric, has been encapsulated in phyto-nanoparticles derived from various plant sources, such as ginger and aloe vera. These nanoformulations have shown enhanced bioavailability, stability, and targeted delivery of curcumin to cancer cells, demonstrating their potential in cancer therapy [21].

Figure 1.

Biomedical applications of phyto-nanoparticles.

In addition to drug delivery, phyto-nanoparticles have also been explored for their potential in imaging and diagnosis. Nanoparticles derived from plants such as tea, grapes, and pomegranate have been found to exhibit fluorescent properties, making them suitable for bioimaging applications [22]. These nanoparticles can be functionalized by targeting ligands to label and image diseased cells or tissues, aiding in the early detection and diagnosis of diseases such as cancer. Moreover, phyto-nanoparticles have shown promise in wound healing and tissue regeneration. Plant-based nanoparticles, such as those derived from aloe vera and ginger, have been found to possess antimicrobial and anti-inflammatory properties [23]. When incorporated into wound dressings or scaffolds, these nanoparticles can promote faster wound healing, reduce the risk of infection, and stimulate tissue regeneration.

Phyto-nanoparticlesare promising in biomedical applications due to their biocompatibility, low toxicity, and versatile properties. With their potential in drug delivery, imaging, and therapy, plant-based nanoparticles offer a sustainable and effective alternative to conventional nanoparticles. As research in this field advances, Phyto-nanoparticles are expected to play an increasingly important role in developing novel biomedical technologies for diagnosing and treating various diseases.

3.2 Advantages of plant-based nanoparticles

The growing utilization of plant sources for nanoparticle fabrication is motivated by their unique advantages:

3.2.1 Sustainability

Using plant sources for nanoparticle fabrication offers a more sustainable and environmentally friendly approach than conventional processes. By avoiding toxic chemicals, phyto-nanoparticle synthesis minimizes the negative environmental impact associated with traditional nanoparticle production. This green approach reduces the generation of hazardous waste and the consumption of non-renewable resources. Using plant-based materials also contributes to the renewable nature of phyto-nanoparticle synthesis, as plants can be cultivated and harvested sustainably, ensuring a continuous supply of raw materials without depleting natural resources. Furthermore, the biodegradability of plant-derived nanoparticles reduces the risk of long-term accumulation in the environment, mitigating potential ecological concerns. Overall, the sustainability advantages of plant-based nanoparticle fabrication align with the growing global emphasis on green chemistry and sustainable manufacturing practices, making it an attractive approach for developing eco-friendly nanomaterials [24].

3.2.2 Biocompatibility

The inherent biocompatibility of plant-based nanoparticles is a significant advantage that facilitates their application in biomedical fields. Plants have evolved to produce a wide range of biomolecules that are intrinsically compatible with human physiology, as many of these compounds are naturally present in our diets. When nanoparticles are synthesized using plant extracts, the biocompatibility of the plant components is transferred to the resulting nanomaterials. Plant-derived biomolecules on the surface of the nanoparticles can also enhance their interaction with cells and tissues, promoting better integration and reducing the likelihood of immune rejection. Moreover, the biodegradability of plant-based nanoparticles ensures that they can be safely metabolized and eliminated from the body after serving their therapeutic purpose, minimizing the potential for long-term accumulation and associated health risks [25]. The biocompatibility of phyto-nanoparticles is particularly advantageous for applications such as drug delivery, tissue engineering, and wound healing, where the nanomaterials are intended to interact closely with living systems. By leveraging the inherent biocompatibility of plant-derived materials, researchers can develop safer and more effective nanomedicines and biomedical devices.

3.2.3 Multifunctionality

One of the critical advantages of plant-based nanoparticles is their multifunctionality, which arises from the diverse range of phytochemicals present in plant extracts. Plants produce many bioactive compounds, including polyphenols, flavonoids, alkaloids, and terpenoids, each with unique therapeutic properties. When these phytochemicals are incorporated into nanoparticles, they impart additional functionalities beyond the basic properties of the nanomaterial itself. Furthermore, encapsulating phytochemicals into nanoparticles can improve their stability, protecting them from degradation and enabling controlled release over an extended period. This enhanced stability and sustained release profile can significantly improve encapsulated compounds’ bioavailability and therapeutic efficacy [26]. The multifunctional nature of phyto-nanoparticles opens up exciting opportunities for developing targeted therapies and multifaceted approaches to address complex medical challenges.

3.2.4 Scalability

The scalability of plant-based nanoparticle production is another significant advantage that makes it an attractive approach for large-scale manufacturing. Plants can be easily cultivated and harvested in large quantities through well-established agricultural practices, providing an abundant and renewable source of raw materials for nanoparticle synthesis. This scalability is crucial for meeting the increasing demand for nanomaterials in various industrial and biomedical applications. Compared to other methods of nanoparticle production, such as chemical synthesis or microbial fermentation, plant-based approaches offer the potential for higher yields and more cost-effective production. Advances in bioengineering and molecular pharming techniques can further enhance the scalability of phyto-nanoparticle production. For example, genetic engineering can develop transgenic plants that overexpress specific phytochemicals of interest, leading to higher yields of the desired compounds. Similarly, optimization of plant growth conditions and extraction processes can improve the efficiency and productivity of nanoparticle synthesis. The ability to scale up plant-based nanoparticle production is particularly relevant for applications that require large quantities of nanomaterials, such as environmental remediation, agricultural interventions, and industrial catalysis. The scalability of phyto-nanoparticle production and the sustainability and cost-effectiveness of plant-based approaches make it a promising avenue for commercially developing nanomaterials.

These integral advantages underpin the promise of plant-based nanoparticle systems to provide sustainable, therapeutic alternatives to conventional nanomaterials. Phyto-nanoparticles constitute a versatile platform to harness the functional benefits of nanotechnology for human healthcare applications [27].

3.3 Disadvantages and limitations of phyto-nanoparticles

Phyto-nanoparticles, synthesized primarily through green synthesis methods using plant extracts, represent a novel class of nanomaterials that combine nanoparticles’ physicochemical properties with plants’ biological attributes. Despite their burgeoning application in the biomedical field, several significant limitations and disadvantages persist, impacting their practical utility and efficacy. One primary concern with phyto-nanoparticles is their complex and often inconsistent synthesis process. While green synthesis is touted for its environmental friendliness, the lack of control over the nanoparticles’ size, shape, and dispersity can result in varied functional properties. This heterogeneity can adversely affect the reproducibility of experimental results and the scalability of production processes [28]. The biological pathways involved in synthesizing phyto-nanoparticles depend heavily on the type of plant extract used, which can introduce variability due to differences in the plants’ concentration and composition of bioactive compounds. These variations make standardizing practices and achieving consistent nanoparticle traits challenging and critical for specific applications, particularly in drug delivery and therapeutic roles.

Moreover, the long-term stability and storage of phyto-nanoparticles pose another significant challenge. Nanoparticles derived from plant sources may be prone to aggregation or degradation over time, diminishing their effectiveness and shelf life. Environmental factors such as temperature, light, and humidity can further exacerbate these stability issues, necessitating sophisticated and often expensive storage solutions to maintain their functional integrity over time [29]. The safety and biocompatibility of phyto-nanoparticles, although generally favorable compared to synthetic nanoparticles, remain areas of concern. The interaction of phyto-nanoparticles with cells and biological systems can sometimes induce cytotoxic effects, particularly at higher concentrations or prolonged exposure. The presence of residual plant materials or contaminants from the synthesis process can also provoke immune responses or inflammatory reactions, which are detrimental in biomedical applications. Additionally, the metabolic pathways involved in degrading and eliminating these nanoparticles from the body are poorly understood, raising concerns about potential bioaccumulation and toxicity [30].

Regulatory challenges also constitute a significant disadvantage. The nanoparticle approval process is stringent and complex, particularly in food and medicine. Phyto-nanoparticles, due to their novel nature, face numerous hurdles in gaining regulatory approval across different jurisdictions. The lack of standardized characterization methods for these nanoparticles further complicates their assessment, requiring extensive and comprehensive studies to establish their safety profiles and therapeutic efficacy. From an application perspective, while phyto-nanoparticles are explored for their potential in various therapeutic and diagnostic roles, their real-world applications are limited by the current understanding of their interactions at the molecular, cellular, and systemic levels. Incomplete knowledge about the mechanisms these nanoparticles exert their effects can limit their design and functional optimization for specific applications. For instance, in drug delivery, the unpredictable release profiles and interaction with biological membranes can result in suboptimal therapeutic outcomes. While phyto-nanoparticles offer several promising advantages, their practical application is hindered by significant limitations related to synthesis variability, stability, safety, regulatory challenges, and incomplete understanding of their biological interactions [31]. Addressing these challenges requires coordinated research efforts to standardize synthesis methods, establish robust safety evaluations, and enhance the functional properties of these nanomaterials for reliable and practical use across various domains.

4. Types of phyto-nanoparticles in osteogenesis

A vast library of plants encompassing food crops, herbs, and their molecular constituents have been transformed into nanocarriers and nanostructures for stimulating stem cell osteogenesis (Figure 2). The rich phytochemical reservoirs serve as building elements for nanoparticle synthesis and confer biofunctional outputs [32]. When appropriately engineered into nanosystems, unique properties emerge from the crosstalk between physicochemical and biological cues that effectively direct bone healing.

Figure 2.

Diverse plant sources for deriving phyto-nanoparticles with osteogenic potential. Phyto-nanoparticles synthesized from various botanical ingredients, including green tea, aloe vera, curcumin, licorice, flavonoids, silymarin, and ginseng, have shown the ability to stimulate osteoblast activity and bone formation. The rich phytochemical composition of these plant sources confers biofunctional properties to the engineered nanoparticles for directing stem cell differentiation and modulating bone cell fates toward enhanced osteogenesis.

4.1 Green tea extract nanoparticles

Green tea, derived from the leaves of the Camellia sinensis plant, has been identified for its numerous benefits. Its high concentration of polyphenolic compounds, specifically catechins, contributes to its antioxidant, anti-inflammatory, and osteogenic activity [33]. Research has proven that tea extract provides considerable safety in preventing neurodegenerative diseases, including Parkinson’s and Alzheimer’s [34]. Additionally, green tea has displayed anti-diabetic properties in animal models [35]. Its antibacterial, anti-HIV, anti-aging, and anti-inflammatory activities have also been documented.

Green tea extract nanoparticles (GTE-NPs) have been shown to have anti-inflammatory effects in animal models. Inflammation is a critical protective mechanism in the healing process. Still, it can also cause pain and swelling associated with pro-inflammatory cytokines such as interleukin (IL) IL-1, IL-6, and tissue necrosis factor-alpha (TNF-α) [36]. GTE-NPs can improve mice’s physiological motor and cognitive function during inflammation, indicating their potential therapeutic applications. They also have antioxidant properties, which can help protect cells from oxidative stress and promote tissue regeneration [33].

GTE-NPs offer potential benefits in bone regeneration due to their unique properties, including antioxidant, anti-inflammatory, and osteogenic effects. Green tea has been reported to promote tissue remodeling and bone healing, making it a promising candidate for enhancing bone regeneration [36]. The catechin (−)-epigallocatechin-3-gallate (EGCG) in green tea facilitates fracture healing and increases bone mineral density, indicating its potential to improve bone health [37]. EGCG enhances the osteogenic differentiation of human bone marrow mesenchymal stem cells through the Wnt signaling pathway, which controls bone development. Additionally, green tea catechins enhance osteogenesis in bone marrow mesenchymal stem cells [38]. Animal experiments have indicated that green tea extract EGCG can significantly stimulate bone regeneration in rat skull defects [39]. Furthermore, GTE-NPs combined with hydroxyapatite create composite materials that exhibit favorable bone regeneration abilities [40]. Potential mechanisms of GTE-NPs in promoting osteogenesis include activation of the Wnt pathway, osteogenic differentiation enhancement, and bone regeneration stimulation [41]. Further research is needed to understand the mechanisms of GTE-NPs in osteogenesis fully, but current findings suggest their potential therapeutic applications for bone regeneration and tissue engineering.

4.2 Aloe vera-based nanoparticles

Aloe vera, a succulent plant species, has been widely recognized for its diverse medicinal applications. The use of aloe vera dates back thousands of years, and its therapeutic properties have been extensively studied. Aloe vera is commonly used topically to treat various skin conditions, including burns, cuts, insect bites, and eczemas, owing to its anti-inflammatory, antimicrobial, and wound-healing properties [42]. Additionally, aloe vera has been investigated as a dietary supplement, with studies suggesting benefits such as reduced dental plaque, accelerated wound healing, and potential glycemic control [43]. Furthermore, oral aloe vera gel has been associated with lowering blood glucose and cholesterol levels, making it attractive for managing diabetes and hyperlipidemia [44]. The plant’s unique properties have also led to research on its potential as a cytotoxic, antitumoral, anticancer, and anti-diabetic agent.

Aloe vera promotes wound healing at the cellular and subcellular levels. It accelerates wound healing by stimulating the proliferation and migration of fibroblasts and keratinocytes, which are essential for repairing injured tissues [45]. Aloe vera nanoparticles (AVNPs) are a recent development in nanotechnology and have gained attention due to their potential biomedical applications. AVNPs have exhibited the potential to promote osteogenesis owing to their unique antioxidant, anti-inflammatory, and osteogenic effects [46]. Gold nanoparticles (AuNPs) synthesized using aloe vera possess osteoinductive properties crucial for bone formation. Using aloe vera in AuNP synthesis provides an eco-friendly and cost-effective approach.

Electrophoretic Deposition of aloe vera-chitosan-hydroxyapatite nanocomposite coatings onto titanium implants was studied [47]. Chitosan was the binding agent, while hydroxyapatite facilitated osseointegration with surrounding bone. Aloe vera particles conferred antibacterial effects against common pathogens like S. aureus, responsible for many implant-associated infections. Excellent biocompatibility was verified by the growth and ALP activity of cultured osteosarcoma cells, making this nanocomposite coating ideal for enhancing the functionality of titanium bone implants. Beyond direct osteogenic stimulation, aloe vera nanoparticles can also play auxiliary roles, such as anti-scarring during bone healing [48]. Aloe vera nanoparticles into a putty containing bioactive glass ceramics and applied as a protective barrier membrane over bone defects. The released aloe vera phytochemicals were found to inhibit myofibroblast differentiation and activity of human dermal fibroblasts via TGF-β1 modulation, thus reducing scar tissue formation while permitting unimpeded bone formation across the defect.

4.3 Curcumin nanoparticles

Curcumin is a chemical compound found in the Curcuma longa plant, also known as turmeric. It is a popular condiment with antioxidant, anti-inflammatory, antimicrobial, and anticancer properties, and it has been widely used in indigenous and traditional medicine [27]. Research suggests that curcumin may help manage oxidative stress, inflammation, metabolic syndrome, arthritis, anxiety, and degenerative eye diseases [49].

In vitro and in vivo studies have demonstrated anti-inflammatory, anti-diabetic, anti-proliferative, and pro-apoptotic effects against various tumors [50]. Curcumin has also exhibited potential against Alzheimer’s, multiple sclerosis, rheumatoid arthritis, atherosclerosis, cataracts, liver damage, lung toxicity, fibrosis, bleeding, clotting, platelet aggregation, and wound healing. However, more bioavailability is needed to ensure its maximal therapeutic potential. Strategies to improve bioavailability include adjuvants like piperine, lipid formulations, structural analogs, and nanoparticulate delivery systems using natural and synthetic polymer-based carriers [51, 52]. These approaches enhance curcumin’s solubility, stability, and absorption to maximize its efficacy.

Nanoparticles of curcumin, also known as nano curcumin, have been extensively researched for improving bioavailability and therapeutic effects. Wet-milling, nanoprecipitation, and other techniques produce nano curcumin with reduced particle size and increased solubility. One study described wet-milled nano curcumin with a narrow size distribution [53], while another emphasized green manufacturing approaches to improve curcumin bioaccessibility [54]. Nanocurcumin formulations have improved efficacy and bioavailability in vivo, making them promising for cancer therapy [55]. Curcumin nanoparticles also have potential applications in dental implantology owing to their antibacterial properties against pathogens like Porphyromonas gingivalis, which commonly cause implant failure [56]. In conclusion, curcumin nanoparticles represent a promising means to enhance the therapeutic potential of curcumin through improved bioavailability and antimicrobial activity. Further research and clinical studies are essential to fully realize their potential while ensuring safety and efficacy for medical and dental uses.

Scaffold fabrication using the curcumin/graphene oxide/hydroxyapatite nanoparticles resulted in sustained curcumin release over a month. Analysis with osteoblast-like MG-63 cells revealed significant upregulation of osteogenic markers like osteopontin and bone sialoprotein compared to pure hydroxyapatite controls, confirming the critical role of released curcumin in driving differentiation [57].

4.4 Other plant-derived nanoparticles

In addition to the well-studied green tea extract, aloe vera-based, and curcumin nanoparticles, researchers have explored numerous lesser-known but promising plant-derived nanoparticles for stimulating bone regeneration. The diverse range of plant-derived nanoparticles presents a promising frontier in osteogenesis. Their unique properties, including bioactivity, biocompatibility, and biodegradability, make them suitable candidates for enhancing bone regeneration and treating bone-related diseases.

4.4.1 Grapefruit extract nanoparticles

Grapefruit extract contains naringin, a flavonoid with antioxidative and anti-inflammatory activities. Naringin nanoparticles promoted osteogenic differentiation of mesenchymal stem cells (MSCs) by upregulating bone morphogenetic protein-2 (BMP-2) and suppressing nuclear factor-kB (NF-kB) [58]. This photo-nanoparticle also increased alkaline phosphatase (ALP) activity, stimulated collagen production, and deposited calcium. Its ability to dually promote osteogenesis and inhibit osteoclastogenesis makes it a promising agent for restoring bone defects [59].

4.4.2 Licorice root nanoparticles

Licorice is a popular herbal medicine containing glabridin, which has estrogenic effects and helps manage postmenopausal osteoporosis. Glabridin nanoparticles enhanced viability and osteogenic differentiation in MSCs by stimulating estrogen receptor signaling [60]. It also inhibited hydrogen peroxide-induced cytotoxicity and reactive oxygen species production. As a phytoestrogen, glabridin is safer than traditional hormone replacement therapy for osteoporosis [61].

4.4.3 Flavonoid nanoparticles

Flavonoids, a diverse group of phytonutrients found in almost all fruits and vegetables, exhibit strong antioxidant properties. The encapsulation of flavonoids into nanoparticles has been explored to enhance their bioavailability and efficacy in osteogenesis [62]. For instance, when formulated into nanoparticles, quercetin, a well-known flavonoid, has significantly improved osteoblast proliferation and differentiation [63]. The enhanced solubility and stability of quercetin nanoparticles facilitate their uptake by bone cells, thereby stimulating the expression of osteogenic markers such as alkaline phosphatase (ALP), osteocalcin, and bone morphogenetic proteins (BMPs).

4.4.4 Silymarin nanoparticles

Silymarin, derived from the milk thistle plant (Silybum marianum), is another phytochemical with potent antioxidant and anti-inflammatory properties. Silymarin nanoparticles have been investigated for their potential in osteogenesis due to their ability to modulate bone metabolism [64]. Studies have demonstrated that silymarin nanoparticles can enhance osteoblasts’ proliferation and mineralization while inhibiting osteoclasts’ formation and activity. By balancing the activities of these cells, silymarin nanoparticles contribute to the maintenance and regeneration of bone tissue, making them a promising candidate for bone tissue engineering and the treatment of osteoporosis [65].

4.4.5 Ginseng nanoparticles

Ginseng, a traditional herbal medicine, contains bioactive compounds called ginsenosides, which have been implicated in various therapeutic effects, including osteogenesis. Ginsenoside-loaded nanoparticles have been designed to overcome the poor bioavailability of ginsenosides, enhancing their therapeutic potential in bone health [66]. These nanoparticles stimulate osteoblast differentiation and bone formation by activating the Wnt/β-catenin signaling pathway. Furthermore, ginseng nanoparticles have been shown to exert immunomodulatory effects, which can significantly benefit conditions characterized by inflammation-induced bone loss, such as osteoporosis and rheumatoid arthritis.

5. Mechanisms of action

Elucidating the mechanistic pathways involved in augmented osteogenic stimulation by phyto-nanoparticles remains an intense research pursuit. Uncovering these mechanisms at the biomolecular and cellular levels provides design feedback better to tailor nanoparticle properties for their intended modulatory roles. Central operating mechanisms encompass direct interactions of the nanoparticles with osteogenic cells to alter differentiation or activity, sustained intracellular delivery of cargo osteogenic drugs, and auxiliary anti-inflammatory and antimicrobial functionality.

The Table 1 summarizes the key processes through which each phyto-nanoparticle influences bone formation and remodeling. These mechanisms include the stimulation of osteoblast differentiation and mineralization, inhibiting osteoclast formation and activity, and modulation of signaling pathways involved in bone metabolism, such as Wnt/β-catenin, RANKL/OPG, BMP, and MAPK. The phyto-nanoparticles listed in the table are flavonoids, curcumin, resveratrol, quercetin, epigallocatechin gallate (EGCG), daidzein, and genistein. It is important to note that each phytonanoparticle may exert its effects through multiple cellular and molecular mechanisms, collectively contributing to the overall process of osteogenesis.

Phyto-nanoparticle	Mechanism of Action in Osteogenesis
Flavonoids	Stimulate osteoblast differentiation and mineralization Inhibit osteoclast formation and activity Enhance bone formation markers (e.g., alkaline phosphatase, collagen)
Curcumin	Promotes osteoblast differentiation and mineralization Suppresses osteoclastogenesis and bone resorption Modulates Wnt/β-catenin signaling pathway
Resveratrol	Enhances osteoblast differentiation and bone formation Inhibits osteoclast differentiation and activity Activates SIRT1 and AMPK signaling pathways
Quercetin	Stimulates osteoblast proliferation and differentiation Inhibits osteoclast formation and bone resorption Modulates RANKL/OPG ratio
Epigallocatechin gallate (EGCG)	Promotes osteoblast differentiation and mineralization Suppresses osteoclast differentiation and activity Regulates BMP and MAPK signaling pathways
Daidzein	Enhances osteoblast proliferation and differentiation Inhibits osteoclastogenesis and bone resorption Activates estrogen receptor signaling
Genistein	Stimulates osteoblast differentiation and bone formation Suppresses osteoclast formation and activity Modulates TGF-β/BMP and Wnt/β-catenin signaling pathways

Table 1.

Mechanisms of action of various Phyto-nanoparticles in osteogenesis.

5.1 Interaction with osteoblasts and osteoclasts

Plant nanoparticles have potential applications in bone remodeling, particularly on osteoblasts and osteoclasts. The studies suggest that the bioactive effects of nanoparticles on bone cells are size, surface property, and composition-dependent. For instance, silica nanoparticles have been demonstrated to improve bone mass and promote the differentiation of bone cells. Similarly, metallic nanoparticles are viable alternatives for bone repair and regeneration due to their bioactivity, biomimetic composition, and good incorporation within the natural bone structure [67]. Orchestrating the coordinated actions of bone-forming osteoblasts and resorbing osteoclasts is critical to developing mature mineralized tissues (Figure 3). Phyto-nanoparticles influence osteogenic outcomes through direct contact with these cells to modulate lineage commitment, differentiation, proliferation, adhesion, and matrix deposition. Particle internalization enables intracellular cargo delivery, while surface coatings present instructive cues to direct cell fate [68]. Nanotopography-mediated contact guidance is emerging as a powerful approach to control stem cell differentiation trajectories. Using green tea polyphenol nanoparticles, Luo et al. [69] described enhanced adhesion, spread, and proliferation in rat mesenchymal stem cells, which correlated with osteogenic marker expression. They postulated that the nanoparticle surfaces provided nanoscale cues resembling fibrillar bone extracellular matrix to promote osteoblastic phenotypes. Inorganic nanoparticles like hydroxyapatite similarly stimulated the fibroblastic differentiation of pre-osteoblastic MC3T3-E1 cells [70].

Figure 3.

Schematic representation of the cellular events occurring at the interface between a phyto-nanocoated implant and bone tissue during the healing process. The illustration depicts the key bone formation and remodeling stages, influenced by phyto-nanoparticles on the implant surface.

Iron oxide nanoparticles have been shown to promote osteoblast differentiation and inhibit osteoclast activity, suggesting a potential role in bone remodeling and regeneration [71]. Iron oxide nanoparticles can be synthesized using plant extracts, which offer a cost-effective, non-toxic, and environmentally friendly approach to obtaining nanoparticles. The biomolecules present in the plant extracts, such as phytochemicals, are responsible for the bioreduction and stabilization of the nanoparticles [72]. The studies suggest that metallic nanoparticles containing plant extracts have been used to treat bone disorders such as osteoporosis. The studies suggest that silver nanoparticles can inhibit differentiation into osteoclasts, indicating their potential as a treatment modality for bone-related diseases.

Besides morphology and adhesion changes, internalized phyto-nanoparticles can directly modulate intracellular signaling proteins and transcription cascades involved in differentiation. For instance, curcumin-gold nanoparticles were found to upregulate Ca2+/NFATc1 signaling through reactive oxygen species generation, consequently increasing alkaline phosphatase activity [73]. Resveratrol nanoparticles amplified miR-21 levels to suppress Smad-7 inhibitory effects on Runx2 and downstream effector activation leading to the commencement of osteoblastic gene expression programs [74]. In addition to osteoblastogenesis, a dynamic equilibrium between bone formation and resorption also necessitates the regulation of multinucleated osteoclasts from monocytic precursors. Undesirable excessive activity leads to net bone loss, compromising repair outcomes. As such, phyto-nanoparticles can target enhanced osteoblastogenesis with attenuated osteoclastogenesis [75]. Silica nanoparticles suppressed osteoclast differentiation and resorptive activity by downregulating NF-κB and interfering with RANK/RANKL signaling that initiates maturation. Meanwhile, hydroxyapatite nanoparticles mitigated reactive oxygen species propagation in osteoblasts subjected to oxidative challenge, preventing premature senescence and enabling sustained matrix deposition [76].

5.2 Drug delivery and sustained release

Plant nanoparticles are emerging as promising drug delivery systems and sustained-release vehicles because they can enhance therapeutic efficacy and mitigate side effects [77]. These nanoparticles, typically 10 to <1000 nm in size, can be engineered to encapsulate drugs and exhibit controlled release properties [78]. The physicochemical characteristics of nanoparticles, including size, surface area, surface chemistry, and shape, significantly impact their interactions within biological systems and are critical design parameters. For example, precise control over size and morphology is required to optimize performance and reduce toxicity. Furthermore, functionalizing the nanoparticle surface with polymers, antibodies, or other ligands facilitates active targeting of specific cells and tissues, thereby improving delivery capabilities [79].

Various nanoparticle platforms, such as lipid, polymer, and peptide nanoparticles, have been developed as drug delivery systems to transport therapeutic agents to intended sites within the body. These systems offer pharmacokinetic advantages compared to free drugs, enable targeting of specific cells, and mitigate off-target effects, thereby improving treatment efficacy [80]. The drug release kinetics can also be engineered by modifying nanoparticle size, surface traits, and composition to achieve sustained and controlled release profiles crucial for chronic therapies [81]. This targeted and sustained drug action reduces drug-induced toxicity while enhancing patient compliance through less frequent dosing regimens, ultimately translating to better patient outcomes. However, the clinical translation of plant nanoparticles warrants further research into the implications of their physicochemical attributes on biological interactions and the development of safe and efficacious drug delivery systems.

Phyto-nanoparticles act as versatile platforms for the intracellular delivery of osteogenic drugs to stimulate implanted scaffold cells or endogenous cells recruited to defect sites. Sustained release perpetuates bioactivity and enhances permeation throughout 3D-engineered tissues [82]. Nanoparticles facilitate passage through cell membranes for efficient internalization and residence within cytosol drug depots. Gradual diffusion or cumulative matrix erosion provides prolonged release kinetics that are optimal for maintaining cell stimulation without adverse effects from sudden bursts. Stimuli-responsive strategies using endogenous or exogenous triggers permit spatiotemporal control over release profiles [83]. Beyond growth factors, small molecule drugs have also been adapted into phyto-nanoparticles. Resveratrol-layered double hydroxide nanohybrids enabled tunable sustained release by diffusion control for over a month [84]. Rat calvarial defect treatment revealed up to 3-fold higher bone volumes than direct injection, confirming enhanced bioavailability and osteogenesis stimulation in vivo via the nanohybrid delivery system [85]. Curcumin nano-formulations similarly amplified therapeutic effects by increasing circulation half-life [86].

5.3 Anti-inflammatory and antimicrobial effects

Phyto-nanoparticles provide auxiliary anti-inflammatory and antimicrobial functionality alongside osteogenic stimulation effects to create optimal microenvironments facilitating repair [87]. Metabolically active compounds like polydatin and protocatechuic acid have been integrated into MSN mesoporous silica nanoparticles to dual-release anti-inflammatory osteogenic drugs [88]. Polydatin nanoparticles suppressed the secretion of inflammatory factors like TNF-α, IL-6, and nitric oxide in LPS-activated macrophages. The anti-inflammatory effects were further enhanced when co-delivered with bone morphogenetic protein two, stimulating mesenchymal stem cell recruitment and local regeneration. These synergistic combinations thus accelerate the resolution of inflammation to progress toward pro-osteogenic conditions [89]. Essential oils containing antimicrobial phytochemicals have been adapted onto osteoconductive bioceramic nanoparticles to combat bacterial infections [90]. Tea tree oil-functionalized magnesium phosphate nanoparticles provided a sustained release of antibacterial oil components alongside facilitating new bone growth [91]. The nanoparticles also induced minimal foreign body reaction and enhanced corrosion resistance compared to pure magnesium. These complementary osteogenic and antimicrobial properties will improve treatment outcomes for infected bone injuries [92].

Plant-mediated nanoparticles have significant anti-inflammatory and antimicrobial properties, making them promising candidates for biomedical applications. Specifically, silver and selenium nanoparticles synthesized using various plant extracts have shown potential as anti-inflammatory agents for treating conditions characterized by inflammation and antimicrobial agents for targeting resistant infections. Silver nanoparticles (AgNPs) synthesized using Aloe vera, green tea, grapefruit, Mentha piperita, and Catharanthus roseus extracts have exhibited anti-inflammatory capabilities [93, 94]. The anti-inflammatory effects make these AgNPs viable options for managing inflammatory ailments. Selenium nanoparticles (SeNPs) prepared using extracts of hawthorn fruit, onion, Thymus vulgaris, Ceropegia bulbosa Roxb, and Diospyros Montana have also demonstrated significant anti-inflammatory properties. These anti-inflammatory SeNPs hold promise as potential agents for treating inflammation-related diseases [95, 96]. Plant-mediated silver and selenium nanoparticles have also displayed broad-spectrum antimicrobial activity against various pathogenic bacteria and fungi. Their potent antimicrobial effects make these nanoparticles candidate alternatives to conventional antimicrobials for tackling drug-resistant infections. Plant-synthesized silver and selenium nanoparticles have shown considerable promise as anti-inflammatory agents for inflammatory diseases and antimicrobial agents for resistant infections [97]. Further research is warranted to translate these nanomaterials into clinical applications as anti-inflammatory and antimicrobial therapeutics.

6. Applications in bone regeneration

Capitalizing on their osteogenic stimulatory effects, phyto-nanoparticles have found widespread applications in designing advanced bone scaffolds, functionalizing orthopedic implants, and therapeutic carriers for bone disease treatments.

6.1 Scaffold materials for bone tissue engineering

Plant-derived nanoparticles are emerging as promising scaffold materials for bone tissue engineering owing to their biomimetic and osteoinductive properties. In particular, biocompatible silica nanoparticles from corn cob and rice husk stimulate osteoblast proliferation and bone growth while inhibiting osteoclasts, making them optimal scaffolds for bone disorders like osteoporosis [98, 99]. Beyond silica, calcium phosphate and gold nanoparticles also possess impressive osteogenic capabilities and have been studied as scaffolds for bone regeneration. For instance, strontium/magnesium-doped calcium phosphate nanoparticles have elicited positive in vitro responses from bone cells, underscoring their potential [100].

Capitalizing on the pro-osteogenic attributes, researchers have developed injectable hydrogels using composites of hydroxyapatite nanoparticles and plant derivatives like silk fibroin, cellulose, and chitosan [101]. Crosslinking chitosan-hydroxyapatite nanoparticles with aloe polysaccharides creates shear-thinning, self-recovery hydrogels suitable for minimally invasive delivery. The macroporous architecture enables bone marrow stem cell infiltration, proliferation, and osteogenic differentiation through controlled release of aloe bioactive phytochemicals, ultimately stimulating functional bone repair in vivo [102].

Plant nanocelluloses fabricated via acid hydrolysis of cellulose fibers also make highly porous bone scaffolds with mechanical integrity rivaling cancellous bones. The concomitant high-water retention facilitates nutrient diffusion and waste removal, enabling osteoblast migration and proliferation with early signs of matrix mineralization [103]. As the nanocelluloses degrade into non-toxic sugars, they mitigate long-term complications. Beyond direct bone formation, aloe polysaccharide nanoparticles delivering pro-angiogenic factors like VEGF from resident osteoblasts can also create vascularized grafts integrated with minimal fibrous scarring [46]. Such intelligently designed phyto-nanoparticles synchronize multiple mechanisms for synergistic bone regeneration.

6.2 Coatings for bone implants

Phyto-nanoparticles hold immense potential for surface modification of bone implants to enhance osseointegration. The current predominant use of bioinert metals like titanium often results in poor host tissue integration, provoking foreign body reactions, leading to fibrotic capsule formation, impairing implant-bone interlock, and providing infectious foci. Phyto-nanoparticle coatings present bioactive interfaces promoting bone cell migration and matrix deposition for accelerated anchorage [104]. Anti-inflammatory ingredients also mitigate immunogenic responses. Phyto-nanoparticle coatings aim to recapitulate multi-factorial extracellular niches by integrating osteoconductive, osteogenic, and anti-infective agents onto implant surfaces. For example, Sabir et al. fabricated zinc-doped hydroxyapatite silica coatings with clove extracts with innate antimicrobial properties. Sustained release of bioactive eugenol compounds inhibited adhesion and destroyed membranes of common pathogens, thus preventing implant-associated infections. The unimpeded growth of osteosarcoma cells also demonstrated excellent cytocompatibility [105].

Seeking dynamic interfaces, Motornov et al. [106] developed self-assembled films containing redox-responsive plant polyphenol nano-capsules on titanium dioxide nanotube arrays formed directly on titanium surfaces. The nano-capsules provided a controlled release of osteogenic and anti-inflammatory agents to stimulate endogenous cell activity. Redox triggers like hydrogen peroxide and ubiquitous glutathione unlocked cargo release by capsule swelling and membrane destabilization. Such innovative delivery systems enable spatiotemporal control, synchronizing therapeutic release profiles in tune with local biological cues [107].

Recent enthusiasm around graphene has sparked interest in phyto-mediated green synthesis of graphene-based implant coatings. Adding silver nanoparticles contributed to anti-infective effects against multidrug-resistant microbes. The accelerated hydroxyapatite deposition and alkaline phosphatase upregulation in osteoblasts cultured on these coatings demonstrated excellent biomineralization. Easy scalability makes such eco-friendly materials attractive for practical translational applications. Plant-derived nanoparticles can be used as coatings on dental and orthopedic implants to enhance their properties and performance. Zirconium nanoparticles from ginger and garlic have shown promise in enhancing dental implants’ antimicrobial, mechanical, and osseointegration properties [108]. Silver nanoparticles from Azadirachta indica (Neem), Aloe vera, Emblica Officinalis (Amla), Cinnamomum camphora extract, and curcumin nanoparticles from turmeric have antimicrobial effects to reduce infections [53, 109, 110, 111]. Zinc oxide nanoparticles from Camellia sinensis have low cytotoxicity and biocompatibility as dental implant coatings [112]. Plant extracts like Aloe vera, green tea, and grapefruit have synthesized gold nanoparticles to improve implant biocompatibility, mechanical properties, antimicrobial activity, and osteoinduction [113].

6.3 Targeted therapy for bone diseases

Bone disorders like osteoporosis and infectious osteomyelitis remain challenging clinical issues as conventional treatments struggle to stimulate regeneration and penetrate dense mineralized matrices. Phyto-nanoparticles present innovative solutions for targeted drug delivery to diseased skeletal sites by protecting cargo drugs from bodily clearance and providing sustained release. Their nanoscale size facilitates extravasation through porous vasculatures nourishing skeletal tissues. Concurrent multimodal imaging enables tracking to verify localization. Seeking osteo-targetability, Liang et al. [114] prepared calcium-deficient hydroxyapatite nanoparticles with high binding affinity to the bone matrix. Covalent tethering of the anti-osteoporotic bisphosphonate alendronate further augmented hydroxyapatite specificity for skeleton tissues. Phyto-sourced berberine alkaloids with anti-osteoporotic effects were then loaded into the nanoparticles. Selective in vivo depot within bone enabled sustained berberine release, stimulating osteoblast differentiation while ameliorating ovariectomy-induced bone loss [112]. Such targeted delivery maximizes therapeutic indexes at diseased sites while avoiding systemic exposure.

Contending with osteomyelitis, Alegrete et al. [115] devised starch-based nanocarriers for bone-selective delivery of vancomycin antibiotics. Cationic surface coatings enabled electrostatic loading of anionic vancomycin molecules with 85% efficiency. Sustained vancomycin release inhibited bacterial growth for a week, reducing inflammatory TNF-alpha and osteoclast activity. Osteoblast proliferation also recovered. Effective infection control coupled with mitigated bone damage illustrates the merits of phyto-nanoparticles for therapeutic delivery, combining innate bioactivity and biocompatibility [113]. In summary, these regenerative medicine niches spanning tissue engineering, implant modification, and drug delivery vehicles provide promising clinical translation pathways capitalizing on emergent phyto-nanotechnology research. A common theme is the recognition of how multifaceted extracellular milieu factors synergistically direct tissue healing outcomes. Appropriately designed phyto-nanoparticles offer intelligently engineered tools integrating biological and physical inputs to stimulate endogenous regenerative responses.

7. Future perspectives and conclusions

Phyto-nanotechnology remains in its early stages, with further innovations in fabrication strategies and biomedical applications necessary to fully tap this vast, untapped potential. Ongoing adoption of personalized medicine approaches appears highly feasible. Additionally, hybrid platforms synergistically combining plant nanoparticles with complementary nanostructures and technologies could engender augmented therapeutic capacities exceeding individual components. In summary, these promising directions forecast next-generation phyto-nanosystems dramatically advancing bone regenerative capabilities and transforming clinical practice. Research fusing plant-based nanomaterials with technologies like 3D bioprinting and externally triggered smart nanoparticles could enable customized patient therapies and enhanced control over healing outcomes. Further research and development focusing on efficacy, safety, and clinical integration will be vital to realizing the full clinical potential of these powerful emerging approaches.

7.1 Innovations in synthesis and application

In recent years, the integration and use of plant-sourced nanoparticles in medicine and dentistry have gained considerable interest. Adopting plant extracts to generate nanoparticles provides multiple benefits over traditional approaches, including cost-effectiveness, environmental sustainability, and control over nanoparticle structure. This method also overcomes nanoparticle clustering during formation, enabling the production of diverse nanoparticle types. Plant-based nanoparticles have shown promise in improving dental implants’ compatibility, durability, and antibacterial properties. Creating bone-targeted nanoparticles and carriers from plants also holds the potential for enhancing osteoporosis treatment by improving drug delivery, minimizing side effects, and boosting the efficacy and safety of osteoporosis medications. The future outlook of plant nanoparticles is promising, with ongoing research on developing new synthesis techniques, characterization methods, and applications. Plant nanoparticles offer advantages over conventional physicochemical preparations, including cost-effectiveness, eco-friendliness, morphology control, and the ability to prevent nanoparticle agglomeration during production for a wide range of nanoparticles.

7.2 Integration with other nanotechnologies

Integrating plant-sourced nanoparticles with other nanostructures, materials, and technologies shows immense potential for synergistic platforms that enhance efficacy beyond individual components. Hybrid nanocomposites combining cellulose, silk, or chitosan phyto-nanoparticles with osteoconductive hydroxyapatites or bioactive glasses can produce scaffolds that mimic complementary aspects of native bone extracellular matrix. This could provide more biomimetic environments to guide bone formation. Incorporating magnetic and plasmonic metal nanoparticles within phyto-nanoparticle matrices could enable external manipulation and stimulation using alternating magnetic fields and laser irradiation. This may allow spatiotemporal control over scaffold activities to better direct cell differentiation and healing. Imaging techniques like surface-enhanced Raman spectroscopy using phyto-reduced gold nanorods also facilitate deeper tracking of bone regeneration in vivo, which is crucial for evaluating translation potential.

Bridging niche applications, fluoride-releasing phyto-nanoparticles could have concurrent antibacterial effects against cariogenic pathogens responsible for dental caries and infections that endanger orthopedic implants. Phyto-nanosystems may also help mitigate bone loss side effects of anticancer medications. Beyond passive carriers, cell membrane-coated phyto-nanoparticles cloaked with blood cell or stem cell membranes may enable biomimetic vehicles for immune system evasion and enhanced tissue penetration. These multifunctional capacities gained from hybridization with emerging nanotechnologies promise innovative solutions for enhanced bone repair. In summary, further research at the intersection of plant biosciences and nanotechnology can realize smarter phyto-nanomaterials designed to synchronize the complex extracellular signals that collectively coordinate optimal healing. Seamless integration into clinical practice promises transformative positive impacts on restoring skeletal function for countless worldwide suffering from bone diseases or injuries.

7.3 Potential in personalized medicine

Inter-patient variability and unique defect microenvironments contribute to inconsistent outcomes using standardized treatments. Transitioning toward personalized medicine paradigms that tailor therapies to individual needs could address these inconsistencies. Readily functionalized phyto-nanoparticles with tunable properties present versatile platforms that enable patient-specific formulations. Nuclear imaging and magnetic relaxation switching may non-invasively track nanoparticle pharmacokinetics and localization within distinct wound sites. This facilitates identifying disease subsets most responsive to particular formulations. Omics profiling discerns proteomic biomarkers and implicated genetic polymorphisms guiding formulation optimization, including specific phytochemical agents targeting dysregulated pathways. Patient-derived cells could determine optimal scaffolded cargo combinations (e.g., cells, genes, drugs) for improved engraftment. 3D bioprinting also enables designing custom macro-architecture and internal porous features adapted to scanned defect volumes. On-demand activation of smart phyto-nanomaterials with external triggers (ultrasound, electromagnetic fields) further permits unprecedented spatiotemporal control over particular cellular stimulation events. These could be programmed in response to personalized healing events like inflammation resolution or cell mobilization waves. Such dynamic, personalized therapies will ultimately improve the consistency and quality of treatment outcomes.

Conflict of interest

The authors declare no conflict of interest.